Styrene ethers of amino alcohols

ABSTRACT

COMPOUNDS OF THE FORMULA   (R&#34;-N(-R&#34;&#39;&#39;)-X-O-CH2-C(=CH2)-),R,R&#39;&#39;-BENZENE   WHEREIN X IS A LOWER ALKYLENE HAVING FROM 2-5 CARBON ATOMS, R AND R&#39;&#39; ARE HYDROGEN, LOWER ALKYL, LOWER ALKOXY OR HALOGEN, R&#34; AND R&#34;&#39;&#39; ARE HYDROGEN, LOWER ALKYL OR PHENYL LOWER ALKYL, AND R&#34; AND R&#34;&#39;&#39; TAKEN TOGETHER WITH N MAY BE PIPERIDINO, MORPHOLINO, THIOMORPHOLINO, PYRROLIDINO, OR METHYLPIPERAZINO, ARE POTENT ANTICONVULSANTS, USEFUL IN THE TREATMENT OF GRAND MAL.

United States Patent Oflice 3,651,067 Patented Mar. 21, 1972 3,651,067 STYRENE ETHERS F AMINO ALCOHOLS Bill Elpern, White Plains, and Victor T. Bandurco, Huntmgtou Station, N.Y., assignors to USV Pharmaceutical Corporation No Drawing. Filed Apr. 15, 1970, Ser. No. 28,985 Int. Cl. C07d 29/18 wherein X is a lower alkylene having from 2-5 carbon atoms, R and R are hydrogen, lower alkyl, lower alkoxy or halogen, R" and R'" are hydrogen, lower alkyl or phenyl lower alkyl, and R" and R taken together with N may be piperidino, morpholino, thiomorpholino', pyrrolidino, or methylpiperazino, are potent anticonvulsants, useful in the treatment of grand mal.

This invention relates to new organic compounds having valuable pharmaceutical activity.

In particular, the invention relates to basic styrene ethers having the structure wherein X is a lower alkylene group having from 2 to 5 carbon atoms, R and R are hydrogen, lower alkyl, such as methyl, ethyl, isopropyl, amyl, and the like, lower alkoxy, such as methoxy, ethoxy, butoxy, and the like, or halogen, and may be the same or different, and R" and R" may be hydrogen, lower alkyl, or phenyl lower alkyl, such as benzyl or phenylethyl, and may be the same or. diflerent, or R", R'", and N taken together may be piperidino, morpholino, thiomorpholino, pyrrolidino, methylpiperazino, and the like. Preferably, X is ethylene or propylene and R and R are hydrogen.

' In accordance with this invention, the compounds are prepared by the reaction of an alcohol of the formula E E5 where R and R are the same as above, with an alkali metal such as, for example, lithium, sodium, or potassium, to form an alkali metal alcoholate, which is then treated with an aminoalkyl halide of the formula where R", R and X are the same as'above and Y is a halogen, such as, chlorine or bromine. Preferably, both stages of the preparation are carried out by heating in an inert solvent.

The reactant alcohols are prepared by oxidizing an appropriately substituted alpha methyl styrene of the formula 3 IQ E R CH wherein R and R are the same as above, with selenium dioxide in acetic acid-acetic anhydride solution followed by saponification of the acetyl derivative to give the free alcohol. ;This method is described in US. Pat. No. 2,537,622.

The compounds of this invention exhibit strong anticonvulsant activity against electroshock induced convulsions in mice according to the method of Swinyard, J. Am. Pharm. Ass. 38, 201 (1949), and are thus particularly useful in the treatment of convulsions in grand mal.

The compounds may be administered as the free bases or as their pharmaceutically acceptable, nontoxic acid addition salts, such as, the hydrochloride, hydrobromide, sulfate, phosphate, acetate, benzoate, cinnamate, citrate, glycolate, mandelate, and the like, in the form of tablets, capsules and elixirs.

The dosage ranges vary from about 5 to 33 mg./kg. when administered subcutaneously to about 20 to 100 mg./ kg. when administered orally.

The invention will be more fully understood from the example which follows, and it is intended to cover all changes and modifications of the example of the invention herein chosen for purposes of disclosure which do not depart from the spirit of the invention.

EXAMPLE 2-piperidino-ethoxy-2- (4-chlorophenyl -propene TABLE I [R and R are hydrogen, X is ethylene] M.P. or B.P./mm., R R" Salt C.

A 136-8 B 92. 5-4. 5 B 81. 5-2. 5 154-58/3 B 111-2 86-90/0. 05 12930/0.01 A 78-80 B 90-92 Morpholino B 96-97 N-methylplperazlno A 196-8 TABLE II [R and R are hydrogen, X is propylene] M.P. or B.P./m m., Salt C.

A 86-90 B 113-5 Et-.- Et 106-8/0.03 2-methylplperidluo A 108-9 TABLE III [R is hydrogen, X is ethylene and R, R" and N is piperldyl] M.P. or B.P./mm., R Salt C.

4-l-Pr 1526/0.2 2-O-Me B 132-4 3-O-Me B 68-70 -O-Me B 52-4 In all tables, A refers to the hydrochloride, and B refers to the oxalate.

t i 3 --We .claim:

wherein R R are selected frorn the group consisting of hydrogen, lower alkyl, lower alkoxy, and halogen,

and may be the same or different, X is a. lower alkylenegroup having from 2 to 5 carbon. atoms, and R,,and Rf are selected fromthe group consisting of; hydrogen, lower alkyl, and phenyl lower aIkyL- and may be the same or dilferent,-and R" and R' takentogether with N are selected from the group consisting of piperidino, morpholino, thiomorpholino, pyrrolidino, and N-methylpiperazrno.

2. A compound according to claim 1, wherein R and R are hydrogen.

T :alkyl g uprh viu from- 4x tlisarhqazatmcfigm 4. A compound according to claim 3, wherein R and R' taken together with Ni is piperidino.

References HENRY R. J Erimary Examiner WINTERS, Assistant Eialfiinel 260-570.6, 247.7 A, 240 K,- 2434 ,-43z 5yr;ag s R, 618 R, 618 D, 618 c, 6131); 294 s; 42 30248 246, 274, 250 

